Prostate cancer is the most common cause of cancer and the second leading cause of cancer deaths in American men. Although most strongly correlated with age and race, family history has also been shown to be an important determinant of prostate cancer risk. The magnitude of the associated risk appears to be dependent upon the number of family members with prostate cancer and the age of prostate cancer onset in affected family members. Genetic linkage studies of high-density prostate cancer families have resulted in the localization of the first prostate cancer susceptibility gene, HPC1, which maps to 1q24-25. Admixture tests suggest that this locus may contribute to prostate cancer susceptibility in less than one-third of high-density prostate cancer families. Replication studies have revealed inconsistent evidence of prostate cancer linkage to this locus; our analysis of 59 families using nonparametric linkage methods has provided the strongest support for the existence of HPC1. In the past six months, two additional prostate cancer susceptibility genes have been proposed: HPC2 at 1q42.2-43 and HPCX at Xq29-28; independent verification of these loci has not been reported. To further support the hypothesis that HPC1 contributes to a significant fraction of hereditary prostate cancer cases and to define the role of other proposed susceptibility loci, including HPC2 and HPCX, and their associated clinical syndromes, the following Specific Aims are proposed: 1.) to examine the characteristics of prostate cancer families that are linked to HPC1 and other HPC loci to determine unique histopathological and clinical features of these families; 2.) to continue to define the role of HPC1 in hereditary prostate cancer; and 3.) to assess the contribution of other potential HPC genes to hereditary prostate cancer, including HPC2 at 1q42.2-43 and HPCX at Xq27-28. These studies will lead to improvements in our understanding of prostate cancer predisposition genes and their associated clinical syndromes.